# Autophagy degradation of nuclear and chromatin constituents

> **NIH NIH R35** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $420,000

## Abstract

PROJECT SUMMARY
 Autophagy is a cell homeostasis process that involves self-digestion of cellular components. The
substrates of autophagy are enclosed in double-membraned autophagosomes that fuse with lysosomes for
degradation. Autophagy is essential for maintaining cell and tissue integrity, and is implicated in a number of
diseases and conditions. While autophagy has been widely studied in degrading cytoplasmic components, its
role in degrading nuclear materials is poorly understood. I recently discovered that autophagy degrades
nuclear lamina in response to tumorigenic stress, such as activated oncogenes and DNA damage. This
autophagic degradation is through nuclear lamina interaction with autophagy proteins in the nucleus, and a
subsequent nucleus-to-cytoplasm transport, leading to degradation by the cytoplasmic autophagosomes and
lysosomes. This discovery was one of the first illustrations of mammalian autophagy degrading nuclear
components, a process termed as nuclear autophagy. The identification of the first nuclear substrate of
autophagy prompted me to further investigate nuclear perspectives of mammalian autophagy.
 Nuclear autophagy is an emerging new field with tremendous potential to explore new research
avenues. A central goal of my laboratory is to study the biology of nuclear autophagy and its implication in
diseases. In this proposal, I aim to answer a major unaddressed area regarding the nuclear substrates that
can be degraded by autophagy. The application has two directions. First, I propose to investigate a chromatin
remodeling complex that is targeted by nuclear autophagy. Second, I propose to unbiasedly identify novel
substrates of nuclear autophagy, employing advanced quantitative proteomics. My broad hypothesis is that the
degradation of nuclear and chromatin constituents by autophagy mediates homeostasis of the nucleus, which
is a central mechanism of cell stress responses. This study will pioneer a new research direction in the
autophagy field, and may offer insights into several intersecting areas of biomedicine.

## Key facts

- **NIH application ID:** 10871853
- **Project number:** 5R35GM137889-05
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Zhixun Dou
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $420,000
- **Award type:** 5
- **Project period:** 2020-08-15 → 2026-03-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10871853

## Citation

> US National Institutes of Health, RePORTER application 10871853, Autophagy degradation of nuclear and chromatin constituents (5R35GM137889-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10871853. Licensed CC0.

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